Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNAseq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated efficacy in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat with histone demethylase inhibitor GSKJ4 revealed synergy. Together, these data suggest a promising therapeutic strategy for DIPG.

Measurements of skeletal muscle cross-sectional area, index, and radiation attenuation utilizing clinical computed tomography (CT) scans are used in assessments of sarcopenia, the loss of skeletal muscle mass and function associated with aging. To classify individuals as sarcopenic, sex-specific cutoffs for ‘low’ values are used. Conventionally, cutoffs for skeletal muscle measurements at the level of the third lumbar (L3) vertebra are used, however L3 is not included in several clinical CT protocols. Non-contrast-enhanced CT scans from healthy kidney donor candidates (age 18–40) at Michigan Medicine were utilized. Skeletal muscle area (SMA), index (SMI), and mean attenuation (SMRA) were measured at each vertebral level between the tenth thoracic (T10) and the fifth lumbar (L5) vertebra. Sex-specific means, standard deviations (s.d.), and sarcopenia cutoffs (mean-2 s.d.) at each vertebral level were computed. Associations between vertebral levels were assessed using Pearson correlations and Tukey’s difference test. Classification agreement between different vertebral level cutoffs was assessed using overall accuracy, specificity, and sensitivity. SMA, SMI, and SMRA L3 cutoffs for sarcopenia were 92.2 cm2, 34.4 cm2/m2, and 34.3 HU in females, and 144.3 cm2, 45.4 cm2/m2, and 38.5 HU in males, consistent with previously reported cutoffs. Correlations between all level pairs were statistically significant and high, ranging from 0.65 to 0.95 (SMA), 0.64 to 0.95 (SMI), and 0.63 to 0.95 (SMRA). SMA peaks at L3, supporting its use as the primary site for CT sarcopenia measurements. However, when L3 is not available alternative levels (in order of preference) are L2, L4, L5, L1, T12, T11, and T10. Healthy reference values reported here enable sarcopenia assessment and sex-specific standardization of SMA, SMI, and SMRA in clinical populations, including those whose CT protocols do not include L3.

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors. A bout 75% of breast cancers express estrogen receptor α (ER), which is a strong driver and therapeutic target for these ER-positive ( + ) tumors. Endocrine therapy with aromatase inhibitors lowers the level of estrogen; selective ER modulators such as tamoxifen (Tam) bind to and block ER, and down-regulators such as fulvestrant (Ful) bind to ER and induce its degradation. Endocrine therapy prolongs disease-free and overall survival when used in the adjuvant setting and can induce long-term remission in some patients in the metastatic setting. Despite the overall success of endocrine therapy, tumors in more than 50% of patients with metastatic disease fail to respond, and nearly all metastatic patients with initially responding tumors eventually experience tumor relapse and die from acquired resistance (1, 2). Although there are many causes for resistance, the most predominant mechanisms include altered ER signaling and interactions between ER, its coregulators, and various growth factor pathways. These alterations facilitate adaptation from ligand-dependent to ligand-independent ER activation, which is further triggered by cross-talk with growth factor receptor (GFR) signaling pathways (3-6). However, the key mediators of ER transcriptional reprogramming in promoting endocrineresistant (Endo-R) breast cancer remain poorly understood.Recently, a potential role of the forkhead box protein A1 (FOXA1) has been suggested in mediating endocrine resistance in breast cancer (7,8). FOXA1 is termed a "pioneer factor" because it binds to highly compacted or "closed" chromatin via a domain similar to that of linker histones and, through its C-terminal domain, renders these genomic regions more accessible to other transcription factors, such as ER (9), progesterone receptor (PR) (10), and androgen receptor (AR) (11). As such, FOXA1 has a key role in demarcating the tissue-specific binding sites of these nuclear receptors (12). Together with ER, FOXA1 contributes to the pattern of gene transcription that induces luminal cell differentiation (13) and represses the basal phenotype (14). Like E...